Pitavastatin is chemically, (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6-heptenoic acid and has the structural formula:

Pitavastatin calcium is a novel member of the medication class of statins. Marketed in the United States under the trade name Livalo, it is like other statin drugs an inhibitor of HMG-CoA reductase, the enzyme that catalyses the first step of cholesterol synthesis. It is likely that pitavastatin will be approved for use in hypercholesterolaemia (elevated levels of cholesterol in the blood) and for the prevention of cardiovascular disease outside South and Southeast Asia as well.
Polymorphism is defined as “the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline structures of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules”. Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning calorimetry (DSC) and Infrared spectrometry (IR).
Solvent medium and mode of crystallization play very important role in obtaining one polymorphic Form over the other.
Pitavastatin and its calcium salt can exist in different polymorphic Forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
Pitavastatin and its process were disclosed in U.S. Pat. No. 5,753,675.
Pitavastatin calcium and its process were disclosed in U.S. Pat. No. 5,856,336.
PCT publication no. WO 2004/072040 (herein after referred to '040 patent) disclosed crystalline polymorph A, polymorph B, polymorph C, polymorph D, polymorph E, polymorph F and amorphous form of pitavastatin calcium.
According to the '040 patent, crystalline polymorph A of pitavastatin calcium was characterized by an X-ray powder diffraction pattern having peaks expressed as 2θ at about 5.0, 6.8, 9.1, 10.0, 10.5, 11.0, 13.3, 13.7, 14.0, 14.7, 15.9, 16.9, 17.1, 18.4, 19.1, 20.8, 21.1, 21.6, 22.9, 23.7, 24.2, 25.2, 27.1, 29.6, 30.2 and 30.2 degrees.
According to the '040 patent, crystalline polymorph B of pitavastatin calcium was characterized by an X-ray powder diffraction pattern having peaks expressed as 2θ at about 4.6, 5.3, 6.2, 7.7, 9.2, 9.6, 10.3, 11.3, 11.7, 12.6, 13.0, 13.9, 14.7, 14.9, 15.6, 16.3, 17.0, 17.4, 18.0, 18.7, 19.3, 20.0, 20.5, 20.8, 21.2, 21.5, 22.4, 23.2, 23.8, 24.4, 25.2, 26.0, 26.4, 27.0, 27.9 and 28.9 degrees.
According to the '040 patent, crystalline polymorph C of pitavastatin calcium was characterized by an X-ray powder diffraction pattern having peaks expressed as 2θ at about 4.1, 5.6, 7.8, 8.3, 10.3, 11.6, 17.5, 17.9, 18.7, 19.5, 20.6, 21.5, 21.9, 23.1, 24.0 and 24.8 degrees.
According to the '040 patent, crystalline polymorph D of pitavastatin calcium was characterized by an X-ray powder diffraction pattern having peaks expressed as 2θ at about 5.0, 6.5, 6.8, 8.7, 10.0, 10.2, 10.8, 13.1, 13.5, 14.3, 15.3, 16.1, 16.8, 18.2, 18.5, 19.0, 19.9, 20.5, 21.0, 21.7, 22.3, 23.4, 24.0, 25.6 and 26.2 degrees.
According to the '040 patent, crystalline polymorph E of pitavastatin calcium was characterized by an X-ray powder diffraction pattern having peaks expressed as 2θ at about 4.4, 5.0, 6.6, 6.8, 8.9, 10.0, 10.3, 10.8, 13.3, 13.6, 14.0, 15.2, 15.9, 16.4, 16.9, 17.8, 18.3, 18.9, 20.2, 20.4, 20.7, 20.9, 21.1, 21.6, 21.7, 22.3, 23.5, 23.8, 24.1, 24.7, 25.4, 26.6, 30.2 and 34.0 degrees.
According to the '040 patent, crystalline polymorph F of pitavastatin calcium was characterized by an X-ray powder diffraction pattern having peaks expressed as 2θ at about 5.1, 5.6, 7.0, 8.8, 9.6, 10.2, 10.9, 11.3, 11.9, 12.5, 13.0, 13.7, 14.4, 14.7, 15.3, 15.5, 16.8, 17.6, 18.3, 19.3, 19.7, 20.6, 21.2, 21.8, 22.8, 23.1, 23.8, 24.1, 24.8, 25.7, 26.2, 26.6, 26.9, 28.4, 29.5, 29.8 and 30.9 degrees.
PCT publication no. WO 2005/063711 disclosed crystal form A of pitavastatin calcium which contains from 5 to 15% of water.
PCT publication no. WO 2007/132482 disclosed a process for the preparation of pitavastatin calcium. According to this process, pitavastatin calcium can be prepared by reacting the (4R,6S)-(E)-6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxane-4-yl}acetic acid tertiary butyl ester in acetonitrile with hydrochloric acid and then treating with sodium hydroxide. The reaction mixture obtained was further treated with methyl amine to form pitavastatin methyl amine salt and then converted to pitavastatin calcium.
PCT publication no. WO 2010/077062 described a process for the preparation of pitavastatin calcium. According to this process, pitavastatin calcium can be prepared by reacting the tert-butyl (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-O-isopropylidene-3,5-dihydroxy-6-heptenoate in acetonitrile with hydrochloric acid and then treating with sodium hydroxide. The reaction mixture obtained was further treated with calcium chloride dihydrate to form pitavastatin calcium.
Tert-butyl-(3R,5S,E)-7-(2-chloropropyl-4-(4-fluorophenyl)quinolin-3-yl)-3,5-dihydroxyhept-6-enoate (pitavastatin tert-butyl ester) is a key intermediate for the preparation of pitavastatin calcium. The chemical formula of pitavastatin tert-butyl ester may be represented as:

The process for the preparation of solid of pitavastatin tert-butyl ester was not disclosed in the prior art. We have discovered that pitavastatin tert-butyl ester can be obtained as a solid. It has been found that the pitavastatin or pharmaceutical acceptable salt of it can be obtained with good chromatographic purity and good yields when the crystalline solid of pitavastatin tert-butyl ester is used for the preparation of the said compounds.
We have also discovered novel crystalline form of pitavastatin calcium. The novel form has been found to be stable over the time and reproducible and so, suitable for pharmaceutical preparations.
Thus, one object of the present invention is to provide a solid of pitavastatin tert-butyl ester and process for its preparation.
Another object of the present invention is to provide a novel crystalline form of pitavastatin calcium, process for its preparation and pharmaceutical compositions comprising it.